Exposure to di(2-ethylhexyl) phthalate inhibits luteal function via dysregulation of CD31 and prostaglandin F2alpha in pregnant mice

Reproductive Biology and Endocrinology

Haibin Kuang¹  Mo Li¹  Lu Zhang¹  Bei Yang¹  Yan Lin²  Teng Zong¹  Lidan Lai¹  Meijun Guo¹ 

[1] Department of Physiology, School of Medicine, Nanchang University, Nanchang, Jiangxi, China;Department of Obstetrics and Gynecology, Hospital of Jixi Province People, Nanchang, Jiangxi, China

关键词: Progesterone;    Pregnancy;    Corpora lutea;    DEHP;   

Others  :  1139701
DOI  :  10.1186/s12958-015-0013-4

 received in 2014-11-05, accepted in 2015-02-23,  发布年份 2015

【 摘 要 】

Background

Di(2-ethylhexyl) phthalate (DEHP) exposure reduces embryo implantations, increases embryonic loss, and decreases fetal body weights. However, whether it is associated with the alteration of luteal function remains unknown. Thus, our aim in this study was to explore the effect and mechanism of DEHP on luteal function in pregnant mice in vivo.

Methods

Mice were administered DEHP by gavage at 125, 250, 500 mg/kg/day from gestational days (GD) 1 to 9 or 13. Levels of serum progesterone and estradiol were measured by radioimmunoassay. The numbers and sizes of corpora lutea were calculated by ovarian histomorphology. Steroidogenic enzymes were assessed by qRT-PCR. CD31 protein was detected by immunocytochemistry, and prostaglandin F2alpha (PGF2alpha) levels were evaluated by enzyme immunoassay.

Results

Treatment with DEHP significantly inhibited progesterone secretion in pregnant mice in a dose-dependent manner but did not inhibit estradiol production on GD 9 and 13. Treatment also showed concomitant decreases in transcript levels for key steroidogenic enzymes (CYP11A, 3β-HSD, and StAR) on GD 13. Furthermore, DEHP administration significantly reduced the numbers and sizes of corpora lutea on GD 13. No significant changes in the ratio of ovary weight vs. body weight were observed between the control group and treated animals on GD 9 and 13. In addition, treatment with DEHP significantly inhibited CD31 expression of corpora lutea, whereas plasma PGF2alpha levels in DEHP treatment groups were significantly higher compared with the control groups on GD 9 and 13.

Conclusions

The results show DEHP significantly inhibits luteal function of pregnant mice in vivo, with a mechanism that seems to involve the down-regulation of progesterone and steroidogenic enzymes message RNA, the decrease in CD31 expression, and the increase in PGF2alpha secretion.

【 授权许可】

   
2015 Guo et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Kamrin MA: Phthalate risks, phthalate regulation, and public health: a review. J Toxicol Environ Health B Crit Rev 2009, 12:157-74.
• [2]Andrade AJ, Grande SW, Talsness CE, Gericke C, Grote K, Golombiewski A, et al.: A dose response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): reproductive effects on adult male offspring rats. Toxicology 2006, 228:85-97.
• [3]Shin IS, Lee MY, Cho ES, Choi EY, Son HY, Lee KY: Effects of maternal exposure to di(2-ethylhexyl)phthalate (DEHP) during pregnancy on susceptibility to neonatal asthma. Toxicol Appl Pharmacol 2014, 274:402-7.
• [4]Lovekamp-Swan T, Davis BJ: Mechanisms of phthalate ester toxicity in the female reproductive system. Environ Health Perspect 2003, 111:139-45.
• [5]Becker K, Seiwert M, Angerer J, Heger W, Koch HM, Nagorka R, et al.: DEHP metabolites in urine of children and DEHP in house dust. Int J Hyg Environ Health 2004, 207:409-17.
• [6]Vo TT, Jung EM, Dang VH, Yoo YM, Choi KC, Yu FH, et al.: Di-(2 ethylhexyl) phthalate and flutamide alter gene expression in the testis of immature male rats. Reprod Biol Endocrinol 2009, 7:104. BioMed Central Full Text
• [7]Chen X, Liu YN, Zhou QH, Leng L, Chang Y, Tang NJ: Effects of low concentrations of di-(2-ethylhexyl) and mono-(2-ethylhexyl) phthalate on steroidogenesis pathways and apoptosis in the murine leydig tumor cell line MLTC-1. Biomed Environ Sci 2013, 26:986-9.
• [8]Doyle TJ, Bowman JL, Windell VL, McLean DJ, Kim KH: Transgenerational effects of di-(2-ethylhexyl) phthalate on testicular germ cell associations and spermatogonial stem cells in mice. Biol Reprod 2013, 88:112.
• [9]Huang LP, Lee CC, Hsu PC, Shih TS: The association between semen quality in workers and the concentration of di(2-ethylhexyl) phthalate in polyvinyl chloride pellet plant air. Fertil Steril 2011, 96:90-4.
• [10]Hannon PR, Peretz J, Flaws JA: Daily exposure to Di(2-ethylhexyl) phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3-kinase signaling pathway in adult mice. Biol Reprod 2014, 90:136.
• [11]Davis BJ, Maronpot RR, Heindel JJ: Di-(2-ethylhexyl) phthalate suppresses estradiol and ovulation in cycling rats. Toxicol Appl Pharmacol 1994, 128:216-23.
• [12]Heudorf U, Mersch-Sundermann V, Angerer J: Phthalates: toxicology and exposure. Int J Hyg Environ Health 2007, 210:623-34.
• [13]Kim SH, Chun S, Jang JY, Chae HD, Kim CH, Kang BM: Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: a prospective case–control study. Fertil Steril 2011, 95:357-9.
• [14]Li R, Yu C, Gao R, Liu X, Lu J, Zhao L, et al.: Effects of DEHP on endometrial receptivity and embryo implantation in pregnant mice. J Hazard Mater 2012, 241–242:231-40.
• [15]Kaul AF, Souney PF, Osathanondh R: A review of possible toxicity of di-2-ethylhexylphthalate (DEHP) in plastic intravenous containers: effects on reproduction. Drug Intell Clin Pharm 1982, 16:689-92.
• [16]Ema M, Miyawaki E: Effects of monobutyl phthalate on reproductive function in pregnant and pseudopregnant rats. Reprod Toxicol 2001, 15:261-7.
• [17]Yochim JM, De Feo VJ: Hormonal control of the onset, magnitude and duration of uterine sensitivity in the rat by steroid hormones of the ovary. Endocrinology 1963, 72:317-26.
• [18]Parillo F, Maranesi M, Brecchia G, Gobbetti A, Boiti C, Zerani M: In vivo chronic and in vitro acute effects of di(2-ethylhexyl) phthalate on pseudopregnant rabbit corpora lutea: possible involvement of peroxisome proliferator-activated receptor gamma. Biol Reprod 2014, 90:41.
• [19]Romani F, Tropea A, Scarinci E, Federico A, Dello Russo C, Lisi L, et al.: Endocrine disruptors and human reproductive failure: the in vitro effect of phthalates on human luteal cells. Fertil Steril 2014, 102:831-7.
• [20]Li N, Liu T, Zhou L, He J, Ye L: Di-(2-ethylhcxyl) phthalate reduces progesterone levels and induces apoptosis of ovarian granulosa cell in adult female ICR mice. Environ Toxicol Pharmacol 2012, 34:869-75.
• [21]Herreros MA, Gonzalez-Bulnes A, Inigo-Nunez S, Contreras-Solis I, Ros JM, Encinas T: Toxicokinetics of di(2-ethylhexyl) phthalate (DEHP) and its effects on luteal function in sheep. Reprod Biol 2013, 13:66-74.
• [22]Herreros MA, Encinas T, Torres-Rovira L, Garcia-Fernandez RA, Flores JM, Ros JM, et al.: Exposure to the endocrine disruptor di(2-ethylhexyl)phthalate affects female reproductive features by altering pulsatile LH secretion. Environ Toxicol Pharmacol 2013, 36:1141-9.
• [23]Stone D, Hechter O: Studies on ACTH action in perfused bovine adrenals: the site of action of ACTH in corticosteroidogenesis. Arch Biochem Biophys 1954, 51:457-69.
• [24]Stouffer RL, Bishop CV, Bogan RL, Xu F, Hennebold JD: Endocrine and local control of the primate corpus luteum. Reprod Biol 2013, 13:259-71.
• [25]Wang X, Shang L, Wang J, Wu N, Wang S: Effect of phthalate esters on the secretion of prostaglandins (F2alpha and E2) and oxytocin in cultured bovine ovarian and endometrial cells. Domest Anim Endocrinol 2010, 39:131-6.
• [26]Ban JB, Fan XW, Huang Q, Li BF, Chen C, Zhang HC, et al.: Mono-(2-ethylhexyl) phthalate induces injury in human umbilical vein endothelial cells. PLoS One 2014, 9:e97607.
• [27]Zei D, Pascarella A, Barrese C, Pantalone S, Stefanini S: DEHP effects on retinal vessels in newborn rats: a qualitative and quantitative analysis. Histochem Cell Biol 2009, 132:567-75.